Method of preparation of 1, 4-pregnadienes



' METHOD OF PREPARATION OF 1,4-PREGNADIENES William S. Allen and Seymour Bernstein, Pearl River, N.Y., assignors to American Cyanamid Company, New York, N .Y., a corporation of Maine No Drawing. Filed Sept. 13, 1956, Ser. No. 609,528

4 Claims. (Cl. 260397.45)

This invention relates to new steroids of the pregnene series and methods of preparation thereof.

The novel compounds of the present invention can be illustrated by the following general formula H in c i XI K\/ a/ l in which XX is a radical selected from the group'consisting of HC C and radicals and R is a member selected from the group consisting of hydrogen and lower alkanoyl radicals.

The present compounds are generally solids having a definite melting point (in excess of 200 C.). They are insoluble in water and soluble in organic solvents such as chloroform, carbon tetrachloride, and the like.

The starting materials used in the process of the present invention are described and claimed in our copending application Serial No. 590,791, filed June 11, 1956, now U.S. Patent 2,806,043. These compounds can be, for example, 115,16a,17a,21-tetrahydroxy-1,4-pregnadione-3,20-dione and the 16a,21-esters thereof.

The compounds of the present invention are useful as intermediates in the preparation of the highly active A pregnadienes of our copending application Serial No. 574,981, filed March 30, 1956, now U.S. Patent 2,789, 118. They can also be used in preparing other steroids, particularly substituted A -pregnadienes.

In preparing the compounds of the present invention, a 160:,21 dilower alkanoyloxy 115,170: dihydroxy 1, 4-pregnadiene-3,20-dione is subjected to the action of a dehydrating agent such as thionyl chloride or phosphorus oxychloride at a temperature of from -15? C. to C. The resulting pregnatn'ene is then treated with an N- bromo-acid amide which can generate in situ the elements of hypobromous acid such as, for example, N-bromoacetamide, N-bromosuccinimide, N- bromophthalimide, and the like at a temperature of 0 to 50 C. to give a 16a,21-dilower a1kanoyloxy-9a-bromo-1 119,17a-dlhYdI'OXY- l,4-pregnadiene-3,20-dione. These latter compounds may be treated underanhydrous conditions in the presence of an anhydrous solvent at refluxing temperatures of the solvent for one to four hours with an alkaline reagent such as potassium acetate, sodium acetate, etc. to remove hydrogen bromide and yield a 16u,21-di1oWer alkanoyloxy 17a hydroxy 96,11 3 oxido 1,4 pregnadiene-3,20-dione.

, ,955,119 2 Patented Oct. 4, 1966 2 The preparation' of the compounds of the present invention in greater detail is described in the following specific examples.

EXAMPLE 1 1 60:,21-a'iacetoxy-I7a-hydr0xy-1,4,9 (11 -pregnatriene- 3,20-di0ne A solution of l6a,21-diacetoxy-11B,17a-dihydroxy-1,4- pregnadiene-3,20-dione (200 mg.) in pyridine (10 ml.)

was chilled to 5, thionyl chloride (1 ml.) was added Analysis.-Calcd for C H O (442.49): C, 67.85; H, 6.83. Found: C, 67.54; H, 7.09.

EXAMPLE 2 1604,21 -diacet0xy-I 7a-hydroxy-9,BJ I 8-0xid0-1 ,4- pregnadiene-3,20-di0ne max.

A solution of 160:,21-diacetoxy-l7a-hydroxy-1,4,9( 11)- pregnatriene-3-,20-dione (200 mg.) in dioxane (10 ml.) and water (2 ml.) was treated with N-bromoacetamide mg.) and 10% perchloric acid (0.42 ml.). After standing for 20 minutes at 20 C., excess sodium sulfite and water was added. The resultant 16a,21-diacetoxyc bromo 11B,17u dihydroxy 1,4 pregnadiene 3, 20-dione was filtered oil and washed with water. This gave 60 mg., melting point 147 (d).

A solution of ,21-diacetoxy-9a-bromo-115,17u-dihydroxy-l,4-pregnadiene-3,20-dione (620 mg.) and potassium acetate (200 mg.) in absolute alcohol (150 ml.) was refluxed for 18 hours. The reaction mixture was evaporated to dryness and the residue extracted with hot ethyl acetate (500 ml.). The extract was washed with saline, dried over anhydrous magnesium sulfate and evaporated. The semi-solid residue was acetylated with pyridine (5 ml.) and acetic anhydride (2 ml.) overnight, after which the mixture was evaporated to dryness. The residue was dissolved in benzene (100 ml.) and chromatographed on silica gel (30 g.). Chloroform eluted the desired product yielding 303 mg. of hard glass. Crystallization from acetone-petroleum ether gave 223 mg., melting point 211-215 C. (42%). Recrystallization from the same solvent pair raised the melting point to 239.5241 C. [m] iO (methanol).

We claim:

1. In a process of preparing 16a,21-diacetoxy-17ahydroxy-9fi,1lfi-oxido-l,4-pregnadiene-3,20-dione, the step which comprises reacting 16a,21-diacetoxy-11/8,17ot-dihydroxy-l,4-pregnadiene-3,20-dione with thionyl chloride and separating the 16u,21-diacetoxy-17a-hydroxy-1,4, 9( 1 1 -pregnatriene-3,20-dione thus obtained.

2. A method of preparing 16a,21-dilower alkanoyl- OXY-L-hYdl'OXY-1,4,9(1 1 -pregnatriene-3,20-dione which comprises reacting l6a,2l-dilower alkanoyl-oxy-11B,17adihydroxy-1,4-pregnadiene-3,20-dione wit-h thionyl chloride in the presence of an organic solvent.

3. A method of preparing 16a,21-diacetoxy-17a-hydroxy-1,4,9 (l 1) -pregnatriene-3 ,20-dione which comprises reacting 16a,21-diacetoxy-11,8,17a-dihydroxy-1,4-pregna- 4. In a process of preparing16a,21-di10wer alkanoyloxy-i 17oc-hyd1'OXY-1,4,9( 1 1 -pregnzitriene-3,20-dione the step Which comprises reacting a 16u,21-dilower alkanoyloxy 11B,17a-dihyt1r0xy 1;4-piegnatriene3 ,20-dio'ne" with thionyl chloride to btain l6a,2l-dilower-alkanoyloxy-17ahydrox-y 1,4,9( 1 1) -pregnatriene-3 ,ZO-dione.

References Cited in the file of this patent UNITED STATES PATENTS Hogg Jan. 10, 1956 Bernstein et a1. Dec. 4, 1956 Bernstein et 01. Dec. 4, 1956 Bernstein et a1. Apr. 16, 1957 Nobile June 3, 1958 Patent No.

(SEAL) Attest:

October 4, 1960 William S. Allen et al.

as corrected below.

lines 32 to 35, teaoI of as in th ERNEST we. SWIDER Attesting ()fficer patent requiring correction and that the said Letters the formula should appear as e patent:

DAVID L. LADD Commissioner of Patents 

1. IN A PROCESS OF PREPARING 16A,21-DIACETOXY-17A-HYDROXY-9B,11B-OXIDO-1,4-PREGNADIENE-3,20-DIONE, THE STEP WHICH COMPRISES REACTING 16A,21-DIACETOXY-11B,17A-DIHYDROXY-1,4-PREGNADIENE-3,20-DIONE WITH THIONYL CHLORIDE AND SEPARATING THE 16A,21-DIACETOXY-17A-HYDROXY-1,4, 9(11)-PREGNATRIENE-3,20-DIONE THUS OBTAINED. 